Drug eluting graft constructs and methods

ABSTRACT

The present invention provides, in certain aspects, medical graft products that incorporate multiple drug depots in and/or on the products. One such product is a sheet graft construct, for example for tissue support that includes a sheet graft material with a plurality of drug depots. The drug depots can be hardened deposits formed directly onto the sheet graft material and/or can be capable of eluting a drug for a minimum of 72 hours.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.14/210,903 filed Mar. 14, 2014 which claims the benefit of U.S.Provisional Application Ser. No. 61/799,080, filed on Mar. 15, 2013,which is incorporated herein by reference in its entirety.

BACKGROUND

The present invention relates generally to medical technology and inparticular aspects to medical graft constructs with the capacity toelute a drug.

As further background, a variety of materials have been used to formimplants, grafts and other medical constructs. These materials includeboth naturally derived and non-naturally derived materials. In somecases, bioremodelable materials including remodelable extracellularmatrix (ECM) materials have been used. Remodelable ECM materials can beprovided, for example, by materials isolated from a suitable tissuesource from a warm-blooded vertebrate, e.g., from the submucosal, dermalor other tissue of a mammal. Such isolated tissue, for example, smallintestinal submucosa (SIS), can be processed so as to havebioremodelable properties and promote cellular invasion and ingrowth.Illustratively, sheet-form SIS material has been suggested and used toform hernia repair grafts and other medical products. Some of thesegrafts exhibit a multiple layer configuration to provide strength and/orreinforcement.

There remain needs for improved and/or alternative medical materials andconstructs, as well as methods for preparing and utilizing the same. Thepresent invention is addressed to those needs.

SUMMARY

The present invention provides, in certain aspects, products thatinclude drug depots carried by a sheet material. The drug depots can, inembodiments herein, include a limited number of depots that incorporatea substantial percentage, for example at least 50% by weight, of thetotal dose of the drug applied to the product.

In certain embodiments, provided is an implantable device that includesa sheet graft material having a top side and a bottom side, and aplurality of drug depots attached to the sheet graft material. The sheetgraft material can include an extracellular matrix sheet material,and/or can have a porous matrix formed by a network of fibers, theporous matrix having pores formed between the fibers of the network. Thedrug depots can comprise solid deposits including a polymeric carrierand a drug. When the sheet graft material has a porous matrix, suchsolid deposits can include a first portion infiltrating pores of theporous matrix and a second portion external of the porous matrix, and/orthe porous matrix can facilitate the distribution of the drug intodepot-free regions of the graft material by diffusion of dissolved,eluted amounts of the drug through the porous matrix. The drug can be anantibiotic agent, for example gentamycin. The drug depots can beconstructed and arranged so as to have the capacity to elute the drugover a time period of at least about 72 hours, or at least about 96hours, when the implantable device is immersed in an aqueous medium suchas an aqueous phosphate buffered saline (PBS) solution at 37° C. The PBScan be a 66.7 mM phosphate buffer saline solution, prepared for exampleas described in Example 1 below. The implantable device can incorporateat least 50%, at least 70%, at least 80%, at least 90%, or essentiallyall (at least 99%), of the total dose of the drug on the device within 2to about 120 depots attached to the sheet graft material, preferablyabout 5 to about 80 depots, and more preferably about 10 to about 60depots. These specified depots can each be constituted of a wafer orother material layer, which can in some forms have at least one widthdimension exceeding about 2 mm and/or occupy a surface area of at leastabout 10 mm².

Additional sheet graft embodiments of the invention are provided whereinthe features of an embodiment as discussed in the paragraph immediatelyabove are combined with one or more features described in the DetailedDescription found below. It is to be understood that the featuresdescribed in connection with specific embodiments set forth in theDetailed Description are contemplated as being capable of generalizationto other embodiments unless clearly indicated otherwise.

Additional embodiments herein relate to methods for preparing one ormore depots on a graft material. In certain aspects, such methodscomprise depositing on a graft material at least one volume, and in somemodes a plurality of volumes, of a flowable material including a drug,and causing the flowable material to harden. In preferred aspects, thesheet graft material includes a porous matrix, and a portion of theflowable material infiltrates the porous matrix, more preferably onlypartially through the thickness of the sheet graft material. Theinfiltrated material is hardened during the hardening step, and forms ahybrid matrix with the porous matrix of the sheet material, which canfacilitate an attachment of the drug depot to the sheet graft material.Such an attached drug depot can include, in addition to the infiltrateddepot material, additional depot material residing outside of the porousmatrix, e.g. extending above a surface of the region of the sheet graftmaterial occupied by the depot.

Still further embodiments herein relate to methods for treating apatient, comprising implanting in the patient an implantable sheet graftdevice as described herein. In certain modes, the sheet graft device isconfigured to support soft tissue of the patient, and is implanted to asto support soft tissue. In some preferred methods, the sheet graftdevice is implanted to support tissue adjacent a body wall defect, suchas a hernia in an abdominal wall or other location in the patient.

Additional objects, embodiments, forms, features, advantages, aspects,and benefits of the present invention shall become apparent from thedetailed description and drawings included herein.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a top view of a medical sheet graft device according to oneembodiment of the invention.

FIG. 2 is a side view of the device of FIG. 1.

FIG. 3 is an enlarged cross-sectional view of a region of the device ofFIGS. 1 and 2 including a drug depot.

FIG. 3A is an enlarged cross-sectional view of a region of the device ofFIGS. 1 and 2 including a drug depot in another embodiment.

FIG. 4 is a partial side view of a sheet graft device during one stageof its manufacture.

FIG. 5 is a partial, side view of the medical product of FIG. 4 at asubsequent stage of manufacture.

FIG. 6 is a perspective view of a medical product according to oneembodiment of the present invention;

FIG. 7 is a cross-sectional view of the product of FIG. 6 along the viewline 7-7 shown in FIG. 6.

FIG. 8 is a top view of another sheet graft device embodiment.

FIG. 9 is a partial cross-sectional view of the product of FIG. 8 alongthe view line 9-9 shown in FIG. 8.

FIG. 10 is an exploded, side view of another sheet graft deviceembodiment.

FIG. 11 is an exploded, side view of another sheet graft deviceembodiment.

FIG. 12 is an exploded, side view of another sheet graft deviceembodiment.

FIG. 13 is a top view of another sheet graft device embodiment.

FIG. 14 is a partial, cross-sectional view of the embodiment of FIG. 13along the view line 14-14 shown in FIG. 13.

FIG. 15 is a partial cutaway top view of another sheet graft deviceembodiment.

DETAILED DESCRIPTION

While the present invention may be embodied in many different forms, forthe purpose of promoting an understanding of the principles of thepresent invention, reference will now be made to the embodimentsillustrated in the drawings, and specific language will be used todescribe the same. It will nevertheless be understood that no limitationof the scope of the invention is thereby intended. Any alterations andfurther modifications in the described embodiments and any furtherapplications of the principles of the present invention as describedherein are contemplated as would normally occur to one skilled in theart to which the invention relates.

As disclosed above, certain aspects of the present invention aredirected to graft products that incorporate multiple drug depots inand/or on the products. These products, in some forms, include a sheetgraft material, e.g., an absorbable or remodelable sheet material suchas extracellular matrix sheet. The sheet graft material can have aplurality of drug depots distributed along an outer surface of thesheet. In certain preferred embodiments, the drug depots are hardeneddeposits that have been created in situ onto the top and/or bottom sideof the sheet, and that can infiltrate at least a portion of thethickness, and preferably only a portion of the thickness, of the sheet.The drug depots incorporate a (at least one) drug and can be capable ofeluting the drug. The drug depots are desirably layer bodies or regularor irregular shapes, for example in the form of circular, ovoid orpolygonal wafers. Desirably, the drug depots are constructed andarranged to elute the drug over an extended period of time. The depotscan be constructed and arranged to elute the drug over a period of timeof at least 72 hours, or at least 96 hours, or at least 168 hours, whenthe device is immersed in an aqueous phosphate buffered saline solution(e.g. as described in Example 1). These same minimum elution times mayalso be achieved in the target implant site for the graft device, e.g. asubcutaneous implant site or when implanted in a body wall, such as theabdominal wall, to repair damaged tissue such as herniated tissue.Elution can occur for example when bodily fluids contact the drug depotsso as to dissolve amounts of the drug, which are then eluted from thedepots. When taking the form of hardened deposits, the drug depots canbe a dried composition including a bioabsorbable polymeric material andthe drug. In some preferred aspects, the drug depots are positioned onthe top surface of the sheet graft material, and taken all togetheroccupy less than about 50% of the sheet's top surface, e.g., in somepreferred forms occupying at least about 5% but less than about 30% ofthe top surface. In some forms, the drug depots will be regularlysituated, e.g., in a repeating pattern, along the top surface of thesheet. In these and other forms, a plurality of thru-openings such asholes or slits can be made through the sheet graft material in regionswhich are unoccupied by the drug depots. Such thru-openings can allowfluid to pass through the sheet graft material from one side to theother. As well, other aspects of the present invention provides methodsfor preparing and using depot-bearing graft constructs, and medicalproducts that include constructs as described herein enclosed withinpackaging in a sterile condition.

With reference now to FIGS. 1 to 3, an inventive sheet graft construct20 is depicted. Construct 20 includes a sheet graft material 21 having atop surface 22 and a bottom surface 23. Construct 20 also includes aplurality of drug depots 24 attached to corresponding depot-bearingregions 25 of the sheet graft material 21, which are surrounded bydepot-free regions 26 of the sheet graft material 21. In the depictedconstruct 20, a portion of the material of the drug depots 24 is locatedinfiltrated within pores between fibers of a porous fibrous matrix ofthe sheet graft material 21, forming a hybrid matrix region 27 includingfibers of the porous fibrous matrix entrained within material of thedrug depots 24. In this fashion, an attachment is created between thedrug depots 24 and the sheet graft material 21. Construct 20 as depictedis generally rectangular in shape having a first edge 28 and acorresponding second, opposite edge 29, and a third edge 30 and acorresponding fourth, opposite edge 31. It will be understood that othershapes for the construct will also be suitable within the invention.Construct 20 also includes a plurality of thru-openings 32 in the formof perforations of generally circular cross-section, to allow fluidpassage through the construct 20 from one side to the other. As shown,in the preferred device thru-openings 32 are located in depot-freeregions of the sheet graft material 21.

Construct 20 also includes a perimeter weaving element 33, such as asuture, extending along the path defined by the outer edges of sheetgraft material 21 and spaced inwardly from the edges, for example by adistance of about 0.1 to about 1 cm. Construct 20 also has an interiorweaving element or elements 34, such as a suture(s), that provide apattern of intersecting weave lines, which in the depicted embodimentform generally rectangular (and particularly here square) shapes acrossthe sheet graft material 21. Where sheet graft material 21 is composedof a laminate including multiple layers, weaving elements 33 and 34 canbe provided and distributed across the graft material 21 to provideresistance to delamination of the layers. The sutures or other weavingelements 33 and 34 can, for example, provide lock stitches that stitchthe layers together for these purposes. A drug depot 24 is locatedwithin each rectangular shape provide by weaving element(s) 34.

In certain preferred aspects, the sheet graft material of construct 20includes multiple ECM layers (e.g., 2 to 10 layers or more), desirablylaminated together as described herein, more desirably by dehydrothermalbonding between ECM layers of the laminate, for example using any of thedehydrothermal bonding techniques described herein. The weavingcomponent(s) are desirably bioabsorbable sutures. Additionally, suchconstructs 20 can incorporate one or more synthetic mesh layers above orbelow any of the ECM layers as described elsewhere herein, e.g., betweenany two ECM layers of the laminate or other multiple layer construct.

Generally, the total surface area defined by the top surfaces of thedrug depots 24, taken together, will be less than the total surface areaof the top surface of the of the sheet graft material 21. In preferredembodiments, the total surface area defined by the top surfaces of thedrug depots, taken together, will be less than 50% of the total surfacearea of the top surface of the of the sheet graft material 24, morepreferably less than about 35%, and even more preferably less than about25%. In certain embodiments, the total surface area defined by the topsurfaces of the drug depots, taken together, will be in the range ofabout 3% to about 50% of the total surface area of the top surface ofthe of the sheet graft material, more preferably in the range of about5% to about 35%, and even more preferably in the range of about 8%, toabout 25%. Again, when drug depots are associated with a sheet graftmaterial, they can be positioned along the top and/or bottom side of thesheet graft material, and/or embedded within the sheet graft material(e.g. between layers of a laminated construct). Thus, in someembodiments, some of the depots can be located on the top and/or bottomof the sheet material while some are embedded within the sheet graftmaterial, and in other embodiments all of the depots can be on an outerexposed surface of the sheet graft material (i.e. top and/or bottom).Sheet graft embodiments having attached depots in accordance of theinvention will thus include depot-free areas or regions between thedepots, which can advantageously present the unmodified sheet graftmaterial to the body of a subject when implanted. Where sheet graftmaterials comprise or are constituted of ECM material or another porousmaterial receptive to cellular invasion, such invasion can occur in thedepot-free areas unaffected by the solid depot material.

The total number of drug depots attached to the sheet graft material canvary. It is preferred that at least a substantial proportion of thetotal dose of drug on the sheet graft device be carried by relativelyfew drug depots. In some aspects, at least 50%, at least 70%, at least80%, at least 90%, at least 95%, at least 99%, or all or essentially allof the total dose of the drug on the device, will be incorporated within2 to about 120 drug depots, preferably about 5 to about 80 drug depots,more preferably about 10 to about 60 drug depots, and even morepreferably about 20 to about 50 drug depots. In some embodiments, thesenumbers of drug depots constitute the total number of drug depots on thedevice.

The drug depots can be substantially the same size as each other (e.g.having top surfaces that have surface areas within about 20% of oneanother) or may vary in size, and the drug depots in some embodimentscan be completely discrete from one another. It will be understood thatwhile completely discrete depots, unconnected to one another by the samematerial from which the depots are formed, are preferred, in otherforms, the depots might be connected to one another by smaller volumesor masses of the depot material such that the majority of the depotmaterial mass on the device is within the depots (e.g. greater than 80%,or 90% by weight). For example, bands or threads of the depot materialmay span between more compact or shaped depot wafers or layers asdescribed herein. These embodiments can nonetheless concentrate the drugto be released in the depot regions, while the overall depot material ofthe device still only occupies a percentage of the surface area of theoverall sheet graft device, e.g. those percentages identified above.

At least some (e.g. two or more, five or more, or ten or more) of theabove-specified drug depots, or all of the above-specified drug depots,can be material layers that have top surfaces with a surface area of atleast about 10 mm², or at least about 20 mm², or at least about 50 mm²,and typically in the range of about 10 mm² to about 1000 mm², moretypically in the range of about 50 mm² to about 500 mm². Additionally oralternatively, at least some (e.g. two or more, five or more, or ten ormore) of the above-specified drug depots can be material layers with atleast one width dimension of at least about 2 mm, more preferably atleast about 4 mm, and typically in the range of about 4 mm to about 20mm; and/or the drug depots can be planar or substantially planarmaterial layers, for example wafers of circular, ovoid, polygonal orother shapes, that when considered in the plane of the material layerhave a first, maximum width taken along a first axis which is no morethan about three times that a second width taken on an axisperpendicular to and centered upon the first axis. Such characteristicscan contribute a preferred, relatively compact shape of the depots.

As an addition or alternative to a consideration of the total number ofthe above-specified drug depots on the sheet graft construct (whichspecified drug depots may incorporate either all or a substantialportion of the total dose of drug on the device, as indicated), thepercentage of the total dose of the drug on the construct that isincorporated in each of the above-specified drug depots can be aconsideration. In certain embodiments, each of the above-specified drugdepots incorporates at least about 0.5% of the total dose of drug on theconstruct, preferably at least about 1%.

The drug depots can be spatially arranged on the sheet graft material ina variety of ways as needed for a particular medical application. Thedrug depots can be arranged in a regular pattern, for example as shownin FIG. 1, or a random or irregular pattern if desired. Some embodimentswill include rows or lines of drug depots. Drug depots may or may not belocated across all parts of a surface, e.g., the top side of a sheetgraft material. Additionally, drug depots can be distributed on thesheet graft material such that upon implantation, eluted drug from thedrug depots diffuses and impregnates the entire sheet graft material. Asubstantially even distribution of the drug depots across the sheetgraft material can be used for these purposes, and/or a porous matrixincorporated into the sheet graft material can facilitate thisdistribution.

In some embodiments, the maximum thickness of at least some of the drugdepots, and potentially all of the depots, will be at least about 25% ofthe maximum thickness of the sheet graft material, or at least about100% of the maximum thickness of the sheet graft material, and typicallyin the range of about 25% to about 500% of the maximum thickness of thesheet graft material. Additionally or alternatively, the averagethickness of at least some of the drug depots, and potentially all ofthe depots, will be at least about 25% of the average thickness of thesheet graft material, or at least about 50% of the average thickness ofthe sheet graft material, and typically in the range of about 25% toabout 500% of the average thickness of the sheet graft material. Aswell, in certain embodiments, such as that depicted in FIGS. 1 to 3, thedrug depots will exposed at the surface of the sheet graft material andwill be situated upon a depot-bearing portion of the sheet graftmaterial. In such embodiments, the drug depots can have an averagethickness (which includes the thickness of any infiltrated portion ofthe depots) that is greater than the average thickness of thecorresponding depot-bearing portion of the sheet graft material. Forexample, the drug depots can have an average thickness that is at least100% of the average thickness of the corresponding depot-bearingportion, and typically in the range of about 100% to 1000% of theaverage thickness of the corresponding depot-bearing portion. Relativelythick drug depots, for example as specified herein, facilitate theprovision of a beneficial extended release of the drug(s) from thedepots.

FIG. 3A shows another drug depot construct that can be incorporated intothe depots of embodiments described herein. The construct of FIG. 3A issimilar to that shown in FIG. 3, only having a top surface of the drugdepot 24 in plane or at least substantially in plane (e.g. varying by nomore than about 2 mm, or no more than about 1 mm, or no more than about0.5 mm above or below) with the top surface of the sheet graft material21 adjacent the drug depot 24. This preferred arrangement can in someembodiments provide a substantially smooth top surface to the overallgraft device (e.g. device 20).

As shown particularly in FIGS. 3 and 3A, when the sheet graft materialhas a porous matrix, material of the formed drug depot can infiltrateand combine with the porous matrix to form a hybrid matrix. Withreference to FIGS. 4 and 5, illustrated is one embodiment of a method bywhich such a structure can be prepared. As shown in FIG. 4, a flowablematerial 40 has been ejected from a dispensing nozzle 41 and formed adeposited volume of material 42 supported by the sheet graft material21. Flowable material 40 incorporates one or more drugs for availabilityin the implantable product, and typically a carrier material such as asynthetic polymeric material. While still flowable, at least a portionof flowable material 40 infiltrates into a porous matrix of the sheetgraft material 21. This can be under pressure caused by the force ofgravity, or other means of pressuring the material 40 may also be used,potentially combined with a wicking action of the porous matrix.However, as discussed above, in preferred embodiments the infiltrationof the material of the depot is only partially through the thickness ofthe sheet graft material 21. Control of the level of penetration can beachieved by consideration of various factors including, for example, theviscosity of the deposited flowable material, the extent of porosity ofthe depot-bearing region of the sheet graft material upon which theflowable material is deposited, the extent of pressure applied to thedeposited material, the residence time of the flowable material on thesheet graft material before hardening, and the like. In some modes ofpractice of the invention, the deposited flowable material caninfiltrate into the sheet graft material a distance that equals at leastabout 1%, or at least about 2%, of the thickness of the correspondingdepot-bearing region of the sheet graft material, and typically in therange of about 1% to about 75% of the thickness of the correspondingdepot-bearing region of the sheet, preferably in the range of about 1%to about 50%, and more preferably in the range of about 1% to about 20%.As well, as discussed above, in some forms of the invention, thedepot-bearing regions of the sheet graft material are denser and/or lessporous than adjacent regions of the sheet graft material. This can helpto prevent undesired levels of penetration of the deposited flowablematerial through the sheet graft material.

FIG. 5 shows an illustrative subsequent stage of manufacture where theflowable material has hardened to a non-flowable solid volume 43, alower portion of which is infiltrated and combined with the porousmatrix of sheet 21. The hardening of the flowable material can be causedby any suitable mechanism. In certain embodiments, such hardening iscaused at least in part, and potentially completely by, removal of aliquid solvent material from the flowable material, for example byevaporation. This can be accomplished for example by any suitable dryingtechnique or techniques, including for example drying at atmosphericpressure and/or under vacuum (subatmospheric pressure). Water and/ororganic solvent materials may be used for these purposes, with volatileorganic solvents, for example acetone, proving beneficial in somemethods. In some modes, a polymeric carrier used to form the depot willbe soluble in the liquid solvent selected while the drug is not and thusexists in the flowable material as a suspended solid particulate.Further, in some variants, the hardening of the deposited flowablematerial will cause the formation of entrapped gas bubbles within thehardened volume 43, forming pores therein. Further, in some modes ofpractice, the manufacture of the depot includes a further step ofcompressing the non-flowable solid volume 43. This can deform andre-shape the volume 43. For example, this can provide a smoother uppersurface to the volume 43 and formed depot, and/or reduce the thicknessof the volume 43 and formed depot, and/or where the volume 43incorporates pores as noted above, can collapse the pores andpotentially densify the volume 43 in the formation of the drug depot. Aswell, during or after such compressing, the volume 43 can be furtherdried, for example under a vacuum and/or with applied heat, to removeadditional amounts of solvent. Such processes can contribute to thedesired elution properties of the drug depot.

With continued reference to FIG. 5, while amounts of the drug depotmaterial can infiltrate at least partially into the depot-bearing regionof the sheet graft material as discussed above, in preferred embodimentsthe formed drug depots also include an amount of drug depot materialexternal of and extending beyond the depot-bearing region of the sheetgraft material.

While the depot formation can include solvent evaporation or otherremoval, as noted above, still other methods for forming the depotseither in situ on the graft material or separately can be used. Forexample, these other methods include deposition of molten mixtures whichharden upon cooling, heated compression casting of dry powder materials,or other suitable methods.

In certain advantageous embodiments, the sheet graft material will havereservoirs into which the flowable, drug-containing material will bedeposited to form the depots. These reservoirs can be formed in thesheet graft material as it is being initially prepared, or can be formedin the sheet graft material after it is prepared, or both, and can havedepths of at least about 0.5 mm, or at least about 1 mm. The thus-formedreservoirs can have a bottom wall and sidewalls. In some forms, a sheetgraft material having a porous matrix is processed to compress selectedregions of the sheet graft material to form these reservoirs. Suchcompression can densify the sheet graft material underlying and formingthe bottom surface of the reservoirs, reducing its porosity. Thisreduced porosity can in certain embodiments at least partially controlthe depth of infiltration of a flowable drug-containing materialdeposited onto the sheet graft material to form a depot, as describedelsewhere herein. In one illustrative reservoir-forming process, a moldpiece having protrusions corresponding to the reservoirs can becompressed into the porous matrix of the sheet graft material, desirablywhen the sheet graft material is in a wetted state. With continuedcompression with the mold piece the sheet graft material can be dried.The reservoirs are thus stably imprinted into the sheet graft material,and remain after the mold or form is removed. Such processing to formreservoirs has been conducted to particular advantage usingextracellular matrix sheet graft material as described herein.

After formation of the reservoirs as noted above, depot-forming materialcan be deposited into the reservoirs. The depot-forming material can atleast partially fill the reservoir, and in some embodiments willcompletely fill the reservoir, potentially with some material providedbeyond that necessary to fill the reservoir. The deposited material cancontact the bottom wall and sidewalls of the reservoir, which will tendto retain the deposited material in the shape of the reservoir. As well,where the sheet graft material includes a porous matrix, due toinfiltration of the depot-forming material into the porous matrix,hybrid matrices including the porous matrix and the depot material canin some embodiments be formed not only in regions adjacent the bottomwalls of the reservoirs as discussed above, but also in regions adjacentthe sidewalls. After deposit of the depot-forming material in thereservoirs, the depot-forming material can be suitably processed, e.g.as described herein, to form a hardened drug depot.

While products with outwardly exposed drug depots like those shown inFIGS. 1 to 3 are highly useful in certain aspects of the presentinvention, it will be understood that such products can in otherembodiments be incorporated into or provide building blocks for othermedical products. For example, a multilayered construct could includemultiple drug-eluting depots on any outer surface of the constructand/or embed multiple depots between any two layers of the construct.Illustratively, a product incorporating the construct in FIGS. 1 to 3could include one or more additional layers, e.g. of a tissue-ingrowthreceptive material, over the top side of sheet material 21 and over drugdepots 24 so as to cover the bodies. The added layer(s) could then beadhered or otherwise anchored to the drug depots 24 and/or the sheetgraft material 21.

While the product of FIGS. 1 to 3 described in relation with FIGS. 4 and5 is illustrative of embodiments in which drug depots are formed assolid deposits of material onto the sheet graft material, in otherembodiments, a drug depot can be created as a separate article and thenattached to the sheet graft material. Depots 24 shown in FIGS. 1 to 3could be separately created and attached to the sheet graft material, tocreate a sheet graft embodiment herein. As another example, FIGS. 6 and7 illustrate another sheet graft medical product 50 according to oneembodiment of the present invention. This particular product includes asheet graft material 51 with a plurality of discrete drug depots 52situated along the sheet's top side 53. Sheet graft material 51 can bemade of any suitable material, with materials that are receptive totissue ingrowth upon implantation in or on the body of a patient beingpreferred, e.g. those described herein. In some particularly preferredembodiments, the sheet graft material will be or incorporate aremodelable material such as a remodelable extracellular matrixmaterial, including any of those described herein.

With continued reference to FIGS. 6 and 7, drug depots 52, in thisillustrative embodiment, are generally disk members with a circularcross-sectional shape, although drug depots can exhibit a variety ofshapes and configurations for example, even including bodies that arerandomly shaped. The depots can be created separately from the sheetmaterial and then subsequently adhered to or otherwise anchored upon thesheet, for example, with an adhesive, preferably a biodegradableadhesive, which adhesive can itself optionally be drug-loaded. The drugdepots can be essentially identical to each other in terms of size,shape, and composition, although this kind of uniformity is certainlynot required in all embodiments herein.

Drug depots 52 or other drug depots to be used herein can be formed withone or more biocompatible materials, including for example bioabsorbableand/or non-bioabsorbable materials, and they can be constructed in anysuitable manner. Suitable formation techniques include but are notlimited to extrusion, hand formation, deposition on a removable backinglayer or other substrate, formation in or on a mold or form and/orcombinations or variations thereof, just to give a few examples. One ormore drugs can be incorporated into such bodies in any suitable mannerincluding, for example, by surface treatment (e.g., spraying, dipcoating, etc.) and/or by impregnation (e.g., soaking) of analready-formed body, or in some cases by mixing one or more drugs into adepot-forming material during a manufacturing step, which can thereafterbe hardened by drying, curing, crosslinking, polymerization or othermeans.

Sheet graft device 50 also includes a plurality of slits 55 formed intothe sheet, although these slits may be absent in other embodiments. Theslits 55 are arranged in a repeating pattern on the sheet graft material51 and are offset from the drug depots 52, i.e., so as to reside inareas unoccupied by the depots. As discussed herein, in addition tothese particular slits, a variety of other slit and non-slitthru-openings can be formed in the sheet graft material.

In some embodiments, a sheet graft material herein will include anextracellular matrix sheet material and a resorbable or non-resorbablesynthetic polymer sheet graft material, for example a synthetic polymermesh or other synthetic polymer layer. FIGS. 8 and 9 illustrate anembodiment combining a synthetic polymer mesh sheet with multipleextracellular matrix layers in accordance with certain aspects of thepresent invention. Sheet graft construct 60 includes a first sheet 61and a second sheet 62 of a collagen-containing extracellular matrixmaterial. A portion of the first or top sheet 61 has been cut away inFIG. 8 to reveal a synthetic mesh material 63 (e.g., polypropylene mesh)disposed between the two sheets 60 and 61. The synthetic mesh includes aplurality of mesh openings 64, and as seen in FIG. 9, the top and bottomsheets 61 and 62 contact one another through the plurality of meshopenings 64 so as to provide a corresponding plurality of contactingregions 65 between the apposed faces of sheets 61 and 62.

While not necessary to broader aspects of this embodiment, in thisillustrative construction, the top and bottom sheets 61 and 62 are alsobonded to one another in regions 65 to provide a plurality of bondedregions 66. By bonding the top and bottom sheets in this manner andaround the peripheral edges of the mesh material, the synthetic meshbecomes sealed within the surrounding ECM sheets. Either ECM sheet, topor bottom, might be formed with a single ECM layer or a multilayered ECMconstruct, for example, a sheet incorporating two, three, four, five,six, seven, eight or more individual ECM layers. Additionally oralternatively, an adhesive (e.g., a drug-loaded adhesive) could be usedto bond the top and bottom sheets together through the mesh openingsand/or to bond the top and/or bottom sheets directly to the syntheticpolymer mesh.

Suitable mesh materials include a large variety of mesh or mesh-likestructures. Thus, relative to what is shown in FIG. 8, a suitable meshcan have, among other things, a different number of openings than mesh63 and/or the shape, size and relative spacing of the openings can beadjusted as desired to suit a particular medical application. Suchfeatures can be used to alter the overall percentage of void space in amesh structure. Illustratively, a mesh opening might be circular, oval,square, rectangular or any other suitable shape.

When incorporated into an inventive graft, a mesh structure, in someembodiments, will be made up of many small filaments, strands or othersmaller pieces of material that are interconnected or otherwiseassociated with one another to form a substantially unitary structurewith mesh openings, e.g., like openings 64. When utilized, these smallerpieces may or may not be bonded or directly connected to one another. Inalternative forms, a mesh may be or include a material that ismanufactured (e.g., by extrusion, in a mold or form, etc.) so as toexhibit essentially a unitary structure. Mesh structures can exhibit aflexibility or compliancy or they can be essentially non-flexible ornon-compliant, in whole or in part. Mesh structures can be essentiallyflat in a relaxed condition, or they can exhibit curvature and/or othernon-planar features, for example, exhibiting a convexo-concavo or otherthree-dimensional shape. A mesh structure, in some aspects, will includemultiple layers of material. When a mesh structure is multi-layered, theindividual layers may or may not be bonded or otherwise connected to oneanother. In some embodiments, an inventive graft will incorporate acoated mesh structure (e.g., coated with a composition comprising a drugand a polymeric material, or coated with a drug and subsequently coatedwith a separate polymer layer, just to give a few examples).

Continuing with FIG. 9, as occurs in contacting regions 65, whenopposing collagen-containing surfaces are in contact with one anothercertain types of advantageous bonding or fusing can occur between thosesurfaces. While the extent and types of contact between such surfacescan vary, for example, depending on the overall number, sizing andrelative spacing of openings in the mesh material, in certain forms, itwill be desirable to fuse or bond the surfaces together to form a moreinterconnected graft body.

In certain embodiments, these contacting collagenous surfaces willdesirably be of a character so as to form an attachment to one anotherby virtue of being dried while compressed against each other. Forexample, dehydration of these surfaces in forced contact with oneanother can effectively bond the surfaces to one another, even in theabsence of other agents for achieving a bond, although such agents canbe used while also taking advantage at least in part on thedehydration-induced bonding. With sufficient compression anddehydration, two collagenous surfaces can be caused to form a generallyunitary collagenous structure. Vacuum pressing operations, and theclosely bonded nature that they can characteristically impart to thecollagen-containing materials, are highly advantageous and preferred inthese aspects of the invention. Some particularly useful methods ofdehydration bonding ECM materials include lyophilization, e.g.freeze-drying or evaporative cooling conditions.

Drug depots can be incorporated into sheet graft construct 50. Forexample, such depots can be any of those disclosed herein, e.g.,independently formed bodies such as those described in conjunction withFIGS. 6 and 7, and/or drug depots formed in situ on the sheet graftmaterial as described in conjunction with FIGS. 1 to 3 and 4-5. Suchdrug depots can be placed or formed between the extracellular matrixsheets 61 and 62, potentially in contact with the synthetic meshmaterial 63, and/or by situating one or more depots along the top and/orbottom surface of the construct 50.

Thus, products with sandwiched or embedded meshes like that shown inFIGS. 8 and 9 can be incorporated into or provide components of othermedical products of the present invention. Illustratively, FIG. 10 showsan exploded, side view of a medical product 70 according to anotherembodiment of the invention. A resorbable or non-resorbable syntheticpolymer mesh 63 (e.g., a polypropylene mesh) is situated between a firstextracellular matrix sheet 61 and a second extracellular matrix sheet 62with an optional drug-containing adhesive layer 71 occurring betweenmesh 63 and the second extracellular matrix sheet 62. A plurality ofdrug depots 72 are situated above the first extracellular matrix sheet61, i.e., opposite the synthetic polymer mesh 63, so that the depots 72are not covered by any other sheet or layer and are therefore leftexposed to the exterior of the product 70. As noted, the drug depots 72can be created separately from the sheet material and then subsequentlyanchored to it, e.g., with a drug-containing or other adhesive, or maybe formed in situ on the extracellular matrix sheet 61 as and includingthe features described herein, either before or after sheet 61 isincorporated into the overall sheet of product 70.

Continuing with FIG. 10, in embodiments where the optional adhesivelayer 71 is omitted, dehydration bonding and/or other bonding techniquesas discussed elsewhere herein can be used to bond the ECM sheets 61 and62 together through openings in the polymer mesh 63 and/or to bond theECM sheets directly to the polymer mesh 63. When an adhesive layer suchas layer 71 is present, it can provide some or all of the bondingbetween the various layers. In respect of the embodiment shown in FIG.10 and all other embodiments disclosed herein made from multipleconstituent pieces, it will be understood that the various pieces can beput together in any suitable order or fashion. In an illustrative methodof manufacture for product 70, the polymer mesh and adhesive layer areplaced between opposing hydrated ECM layers, and this entire structureis then subjected to compression under dehydration conditions.Subsequently, the drug-eluting bodies are adhered to or formed in situonto the top surface of the dried hybrid structure. Optionally, product70 itself can be incorporated into or provide a building block for othermedical products of the present invention. For example, in analternative embodiment, a second synthetic polymer layer (e.g., aresorbable or non-resorbable polymer mesh) can be positioned between thefirst ECM sheet 61 and the drug depots 72 and/or a third ECM sheet couldbe positioned over the drug-eluting bodies 72. Optionally, in any ofthese embodiments, a second group of drug-eluting bodies could besituated below and attached to the second ECM sheet 62.

FIG. 11 shows an exploded, side view of a sheet graft medical product 80according to another embodiment of the invention. A synthetic polymermesh 63 is situated between a first extracellular matrix sheet 61 and asecond extracellular matrix sheet 62. Additionally, a first group ofdrug-eluting bodies 81 is situated between the first extracellularmatrix sheet 61 and a third extracellular matrix sheet 82, while asecond group of drug-eluting bodies 83 is situated between the secondextracellular matrix sheet 62 and a fourth extracellular matrix sheet84. Again, the various illustrative components can be bonded orotherwise affixed together in any suitable manner including thosedescribed herein, and product 80 itself can be incorporated into orprovide a component for other medical products of the present invention.

FIG. 12 shows an exploded, side view of a medical product 90 accordingto another embodiment of the invention. A distinct drug-containingadhesive layer 91 is situated between a synthetic polymer mesh 63 and anextracellular matrix sheet 62. Additionally, a plurality of drug-elutingbodies 92 are situated above the synthetic polymer mesh 63, i.e.,opposite the extracellular matrix sheet 62, so that the bodies are notcovered by any other sheet or layer and are therefore left exposed tothe exterior of the product. Optionally, product 90 itself can beincorporated into or provide a building block for many other medicalproducts of the present invention. In an alternative embodiment, asecond group of drug-eluting bodies could be situated below the ECMsheet 62 and/or a second ECM sheet could be positioned over thedrug-eluting bodies 92.

FIGS. 13 and 14 depict an illustrative graft construct 100 thatincorporates a synthetic mesh material 63, for instance similar to thatshown in FIG. 9. In this embodiment, the synthetic mesh 63 is totallyencapsulated between and within a top ECM layer 61 and a bottom ECMlayer 62. While the actual material of the encapsulated mesh is hiddenfrom view in the completed construct, the contour of the externalsurface of the construct forms depressions within the openings andprotuberances over the mesh elements. This makes it possible to discernthe location of the mesh openings, through which the opposing ECM layershave been bonded together to form bonded regions 66. It should beunderstood however that the shape of a bonded region need not correspondto the shape of an underlying synthetic mesh opening, although this willgenerally be the case where ECM sheets are pressed in close proximityaround a synthetic mesh and bonded together through openings in themesh. Also, because the synthetic mesh is slightly smaller in area thanthe ECM sheets, the full bonding together of the opposing ECM layersproduces a band 101 of bonded material around the entire periphery ofthe synthetic mesh. This band is a multilayered bonded ECM region devoidof synthetic mesh material.

A plurality of discrete drug depots 102 have been formed directly ontothe top of the graft. While not necessary to broader aspects of theinvention, in this embodiment, each depot 102 is positioned over one ofthe bonded regions 66. Additionally, with this particular design, asingle passageway 103 extends through all of the bonded regions exceptthose covered by a depot 102 although passageways could be placed atthose locations as well. Passageways 103 include a passageway wall 104that traverses the entire thickness of the ECM-synthetic meshcombination. As can be seen in FIG. 13, each passageway is generallycentered within a corresponding bonded region 66, and the area of thebonded region 66 is considerably larger than the diameter of thepassageway 103 such that, when viewed from the top, the bonded regionarea extends laterally beyond and fully around the passageway. Eachgenerally cylindrical passageway extends through a corresponding openingof the mesh although a 1:1 ratio of passageways to synthetic meshopenings is not required. A particular synthetic mesh opening or bondedregion might have two or more passageways associated with it, or itmight have none associated with it.

With sufficient bonding between the top and bottom ECM sheets wherethese sheets meet along the passageway wall 104, the passageway can besubstantially isolated from the material of the synthetic mesh 63. Thiscan allow, for example, bodily fluid and other substances to more easilypass from one side of the graft to the other without being able todirectly contact the synthetic material 63, or at least not for someperiod of time following implantation. By using various bondingtechniques as discussed herein, the ECM sheets can be bonded together tothe point of essentially sealing off the passageway from the syntheticmesh. Additionally, the passageway wall 104 can be lined or coated witha variety of substances, e.g., waxes, oils or absorbable polymers suchas PLGA to help further separate or block the passageway from thesynthetic mesh 63 if desired.

FIG. 15 depicts an inventive graft construct 110 that incorporates anoptional synthetic polymer mesh 63 disposed between a top sheet 61 andbottom sheet 61. The top and bottom sheets 61 and 62 are eachconstructed of multiple ECM layers, e.g., 2-10 or more individual ECMlayers. A drug depot 111 has been formed in situ or otherwise attachedonto top sheet 61. A plurality of such drug depots can be attached tothe top and/or bottom of the graft constructs in a variety of locationsas discussed elsewhere herein. An optional interweaving member 112(e.g., bioabsorbable suture) affixes the top and bottom sheets together,and in instances where the top and bottom sheets are laminated together,can provide the function of helping to prevent their prematuredelamination. One or more interweaving members of this sort can beincorporated into any of embodiments disclosed herein. For example,interweaving members such as those illustrated in InternationalApplication No. PCT/US2011/063588 (Cook Biotech Incorporated), filedDec. 6, 2011, which is hereby incorporated by reference in its entirety,can be incorporated into any of the inventive product disclosed hereinto provide some level of fixation between any two or more components inthe product. Also, as described elsewhere herein, any suitable numberand type of slit and non-slit openings can be formed into the productextending fully or partially through any layer of the product.

Continuing with FIG. 15, in one illustrative method of manufacturingthis particular embodiment, the synthetic mesh 63 is sandwiched betweenthe top and bottom sheets 61 and 62 (e.g., before any lamination occursbetween the top and bottom sheets and/or between the individual ECMlayers within each of the top and bottom sheets), and then all of theindividual ECM layers are laminated together with the synthetic mesh 63inside. When included, the interweaving member 112 provides furtherfixation of the laminated ECM layers. Alternatively, the top and bottomsheets 61 and 62 could be prepared separately by dehydrothermallybonding or otherwise laminating their individual ECM layers together,and when included, the mesh 63 could then be inserted between thepreviously-prepared sheets. Subsequent bonding of the top and bottomsheets (e.g., with dehydrothermal bonding, use of adhesives and othertechniques) and/or installation of one or more interweaving memberscould then be performed.

In preferred forms, sheet graft materials herein will exhibit acompliancy, particularly when wet, so as to be conformable to tissuestructures or regions within a patient to be treated. Sheets graftmaterials herein can be essentially planar in a relaxed condition, orthey can exhibit curvature and/or other non-planar features, forexample, exhibiting a curved, convex or other three-dimensionalconfiguration.

A sheet graft material, in some embodiments, will be a laminate madefrom multiple layers of material, for instance 2 to 20 layers ofmaterial, or 2 to 10 layers of material in certain forms. In a laminatesheet, the constituent layers may all be identical, or any one layer maybe the same or different than any other layer in terms of itsmaterial(s) of construction and/or any other characteristic.Illustratively, suitable laminate structures can include a plurality ofECM layers bonded together, a plurality of non-ECM layers (e.g.,biodegradable or non-biodegradable synthetic polymer layers) bondedtogether, or a combination of one or more ECM layers and one or morenon-ECM layers bonded together. Illustratively, two or more ECM sheetscan be bonded together using a bonding technique, such as chemicalcross-linking or vacuum pressing under dehydrating conditions. Anadhesive, glue or other agent may also be used in achieving a bondbetween material layers. Suitable bonding agents may include, forexample, collagen gels or pastes, gelatin, or other agents includingreactive monomers or polymers, for example cyanoacrylate adhesives. Acombination of one or more of these with dehydration-induced bonding mayalso be used to bond ECM material layers to one another.

The drug or drugs incorporated in the drug depots can be any of a widevariety of known useful drugs. The drug can be an antimicrobial agent.Illustrative antimicrobial agents include, for example, antibiotics suchas penicillin, tetracycline, chloramphenicol, minocycline, doxycycline,vancomycin, bacitracin, kanamycin, neomycin, gentamycin, erythromycinand cephalosporins. Examples of cephalosporins include cephalothin,cephapirin, cefazolin, cephalexin, cephradine, cefadroxil, cefamandole,cefoxitin, cefaclor, cefuroxime, cefonicid, ceforanide, cefotaxime,moxalactam, ceftizoxime, ceftriaxone, and cefoperazone, and antiseptics(substances that prevent or arrest the growth or action ofmicroorganisms, generally in a nonspecific fashion) such as silversulfadiazine, chlorhexidine, sodium hypochlorite, phenols, phenoliccompounds, iodophor compounds, quaternary ammonium compounds, andchlorine compounds. Still other drugs can be incorporated in the drugdepots, alone or in combination with an antimicrobial agent or eachother. Such other drugs may include, for example, anti-clotting agents(e.g. heparin), anti-inflammatory agents, anti-proliferative agents(e.g. taxol derivatives such as paclitaxel), inhibitors of tissueadhesions, nonsteroidal anti-inflammatory drugs (NSAIDs), and others.

Turning now to a more detailed discussion of materials that can beutilized in the present invention, as discussed elsewhere herein,inventive constructs can incorporate naturally derived and/ornon-naturally derived materials. In this regard, one or more componentsof an inventive construct (e.g., a sheet, layer, mesh, drug-elutingdepot, just to name a few) may comprise one or more of a variety ofsynthetic polymeric materials including but not limited to bioresorbableand/or non-bioresorbable plastics. Bioresorbable or bioabsorbablepolymers that may be used include, but are not limited to, poly(L-lacticacid), polycaprolactone, poly(lactide-co-glycolide),poly(hydroxybutyrate), poly(hydroxybutyrate-co-valerate), polydioxanone,polyorthoester, polyanhydride, poly(glycolic acid), poly(D,L-lacticacid), poly(glycolic acid-co-trimethylene carbonate),polyhydroxyalkanaates, polyphosphoester, polyphosphoester urethane,poly(amino acids), cyanoacrylates, poly(trimethylene carbonate),poly(iminocarbonate), copoly(ether-esters) (e.g., PEO/PLA), polyalkyleneoxalates, and polyphosphazenes. These or other bioresorbable materialsmay be used, for example, where only a temporary function or presence isdesired, and/or in combination with non-bioresorbable materials whereonly a temporary participation by the bioresorable material is desired.Bioabsorable polymers, such as those identified above, are preferredmaterials to serve as carriers for drug depots herein, and/or in certainembodiments may also be used to form bioabsorbable synthetic polymermeshes used in embodiments herein.

Non-bioresorbable, or biostable polymers that may be used include, butare not limited to, polytetrafluoroethylene (PTFE) (including expandedPTFE), polyethylene terephthalate (PET), polyurethanes, silicones, andpolyesters and other polymers such as, but not limited to, polyolefins,polyisobutylene and ethylene-alphaolefin copolymers; acrylic polymersand copolymers, vinyl halide polymers and copolymers, such as polyvinylchloride; polyvinyl ethers, such as polyvinyl methyl ether;polyvinylidene halides, such as polyvinylidene fluoride andpolyvinylidene chloride; polyacrylonitrile, polyvinyl ketones; polyvinylaromatics, such as polystyrene, polyvinyl esters, such as polyvinylacetate; copolymers of vinyl monomers with each other and olefins, suchas ethylene-methyl methacrylate copolymers, acrylonitrile-styrenecopolymers, ABS resins, and ethylene-vinyl acetate copolymers;polyamides, such as Nylon 66 and polycaprolactam; alkyd resins,polycarbonates; polyoxymethylenes; polyimides; polyethers; epoxy resins;polyurethanes; polypropylene; rayon; and rayon-triacetate. In certainembodiments, biostable polymers can be used as carriers in drug depotsand/or meshes incorporated in embodiments herein.

As disclosed above, in certain embodiments, the sheet graft materialwill include a remodelable material. Particular advantage can beprovided by devices that incorporate a remodelable material. Suchremodelable materials can be provided, for example, by collagenousmembrane layer materials isolated from a warm-blooded vertebrate, andespecially a mammal. Such isolated collagenous membrane materials can beprocessed so as to have remodelable, angiogenic properties and promotecellular invasion and ingrowth. Remodelable materials may be used inthis context to promote cellular growth on, around, and/or in bodilyregions in which inventive devices are implanted or engrafted.

Suitable remodelable materials for incorporation in any of theembodiments herein can be provided by collagenous extracellular matrix(ECM) materials. For example, suitable collagenous materials include ECMmaterials such as those comprising submucosa, renal capsule membrane,dermal collagen, dura mater, pericardium, fascia lata, serosa,peritoneum or basement membrane layers, including liver basementmembrane. Suitable submucosa materials for these purposes include, forinstance, intestinal submucosa including small intestinal submucosa,stomach submucosa, urinary bladder submucosa, and uterine submucosa.These or other ECM materials can be characterized as membranous tissuelayers harvested from a source tissue and decellularized. Thesemembranous tissue layers can have a porous matrix comprised of a networkof collagen fibers, wherein the network of collagen fibers retains aninherent network structure from the source tissue. In particularaspects, collagenous matrices comprising submucosa (potentially alongwith other associated tissues) useful in the present invention can beobtained by harvesting such tissue sources and delaminating thesubmucosa-containing matrix from smooth muscle layers, mucosal layers,and/or other layers occurring in the tissue source, and decellularizingthe matrix before or after such delaminating. For additional informationas to some of the materials useful in the present invention, and theirisolation and treatment, reference can be made, for example, to U.S.Pat. Nos. 4,902,508, 5,554,389, 5,993,844, 6,206,931, and 6,099,567.

Submucosa-containing or other ECM tissue, when used in the invention, ispreferably highly purified, for example, as described in U.S. Pat. No.6,206,931 to Cook et al. Thus, preferred ECM material will exhibit anendotoxin level of less than about 12 endotoxin units (EU) per gram,more preferably less than about 5 EU per gram, and most preferably lessthan about 1 EU per gram. As additional preferences, the submucosa orother ECM material may have a bioburden of less than about 1 colonyforming units (CFU) per gram, more preferably less than about 0.5 CFUper gram. Fungus levels are desirably similarly low, for example lessthan about 1 CFU per gram, more preferably less than about 0.5 CFU pergram. Nucleic acid levels are preferably less than about 5 μg/mg, morepreferably less than about 2 μg/mg, and virus levels are preferably lessthan about 50 plaque forming units (PFU) per gram, more preferably lessthan about 5 PFU per gram. These and additional properties of submucosaor other ECM tissue taught in U.S. Pat. No. 6,206,931 may becharacteristic of any ECM tissue used in the present invention.

Submucosa-containing or other remodelable ECM tissue material may retainone or more growth factors native to the source tissue for the tissuematerial, such as but not limited to basic fibroblast growth factor(FGF-2), transforming growth factor beta (TGF-beta), epidermal growthfactor (EGF), cartilage derived growth factor (CDGF), and/or plateletderived growth factor (PDGF). As well, submucosa or other ECM materialswhen used in the invention may retain other native bioactive agents suchas but not limited to proteins, glycoproteins, proteoglycans, andglycosaminoglycans. For example, ECM materials may include nativeheparin, native heparin sulfate, native hyaluronic acid, nativefibronectin, native cytokines, and the like. Thus, generally speaking, asubmucosa or other ECM material may retain one or more native bioactivecomponents that induce, directly or indirectly, a cellular response suchas a change in cell morphology, proliferation, growth, protein or geneexpression.

Submucosa-containing or other ECM materials can be derived from anysuitable organ or other tissue source, usually sources containingconnective tissues. The ECM materials processed for use in the inventionwill typically be membranous tissue layers that include abundantcollagen, most commonly being constituted at least about 80% by weightcollagen on a dry weight basis. Such naturally-derived ECM materialswill for the most part include collagen fibers that are non-randomlyoriented, for instance occurring as generally uniaxial or multi-axialbut regularly oriented fibers. When processed to retain native bioactivefactors, the ECM material can retain these factors interspersed assolids between, upon and/or within the collagen fibers. Particularlydesirable naturally-derived ECM materials for use in the invention willinclude significant amounts of such interspersed, non-collagenous solidsthat are readily ascertainable under light microscopic examination withappropriate staining. Such non-collagenous solids can constitute asignificant percentage of the dry weight of the ECM material in certaininventive embodiments, for example at least about 1%, at least about 3%,and at least about 5% by weight in various embodiments of the invention.

A submucosa-containing or other ECM material used in the presentinvention may also exhibit an angiogenic character and thus be effectiveto induce angiogenesis in a host engrafted with the material. In thisregard, angiogenesis is the process through which the body makes newblood vessels to generate increased blood supply to tissues. Thus,angiogenic materials, when contacted with host tissues, promote orencourage the formation of new blood vessels into the materials. Methodsfor measuring in vivo angiogenesis in response to biomaterialimplantation have recently been developed. For example, one such methoduses a subcutaneous implant model to determine the angiogenic characterof a material. See, C. Heeschen et al., Nature Medicine 7 (2001), No. 7,833-839. When combined with a fluorescence microangiography technique,this model can provide both quantitative and qualitative measures ofangiogenesis into biomaterials. C. Johnson et al., Circulation Research94 (2004), No. 2, 262-268.

Further, in addition or as an alternative to the inclusion of suchnative bioactive components, non-native bioactive components such asthose synthetically produced by recombinant technology or other methods(e.g., genetic material such as DNA), may be incorporated into an ECMmaterial. These non-native bioactive components may be naturally-derivedor recombinantly produced proteins that correspond to those nativelyoccurring in an ECM tissue, but perhaps of a different species. Thesenon-native bioactive components may also be drug substances.Illustrative drug substances that may be added to materials include, forexample, anti-clotting agents, e.g. heparin, antibiotics,anti-inflammatory agents, thrombus-promoting substances such as bloodclotting factors, e.g., thrombin, fibrinogen, and the like, andanti-proliferative agents, e.g. taxol derivatives such as paclitaxel.Such non-native bioactive components can be incorporated into and/oronto ECM material in any suitable manner, for example, by surfacetreatment (e.g., spraying) and/or impregnation (e.g., soaking), just toname a few. Also, these substances may be applied to the ECM material ina premanufacturing step, immediately prior to the procedure (e.g., bysoaking the material in a solution containing a suitable antibiotic suchas cefazolin), or during or after engraftment of the material in thepatient.

In certain forms, inventive devices include a material receptive totissue ingrowth. Upon deployment of such devices in accordance with thepresent invention, cells from the patient can infiltrate the material,leading to, for example, new tissue growth on, around, and/or within thedevice. In some embodiments, the device comprises a remodelablematerial. In these embodiments, the remodelable material promotes and/orfacilitates the formation of new tissue, and is capable of being brokendown and replaced by new tissue. Remodelable ECM materials having arelatively more open matrix structure (i.e., higher porosity) arecapable of exhibiting different material properties than those having arelatively more closed or collapsed matrix structure. For example, anECM material having a relatively more open matrix structure is generallysofter and more readily compliant to an implant site than one having arelatively more closed matrix structure. Also, the rate and amount oftissue growth in and/or around a remodelable material can be influencedby a number of factors, including the amount of open space available inthe material's matrix structure for the infusion and support of apatient's tissue-forming components, such as fibroblasts. Therefore, amore open matrix structure can provide for quicker, and potentiallymore, growth of patient tissue in and/or around the remodelablematerial, which in turn, can lead to quicker remodeling of the materialby patient tissue. In certain aspects, an extracellular matrix layer ormultilayer sheet (e.g. a laminate) includes an open matrix structureformed by lyophilization drying of the layer or sheet.

In certain embodiments, the sheet graft material can include two or moreindividual layers of ECM material (e.g., 2 or more layers bondedtogether). The total thickness of such a sheet can be in the range ofabout 200 microns to about 4,000 microns, e.g., more than about 400microns, or more than about 600 microns, or more than about 800 microns,or more than about 1,000 microns, or more than about 1,200 microns, ormore than about 1,500 microns but typically less than about 2,000microns. In certain aspects, 2 to about 20 layers of ECM material arebonded in a laminate for use as or in the sheet graft material, morepreferably 2 to about 10 layers of ECM material.

The constructs described herein have broad application. In some aspects,inventive products will find use as precursor materials for the laterformation of a variety of other medical products, or components thereof.Medical grafts and materials that are already commercially available canbe modified in accordance with the present invention as well. In certainembodiments, inventive products are useful in procedures to replace,augment, support, repair, and/or otherwise suitably treat diseased orotherwise damaged or defective patient tissue. Some of the illustrativeconstructs described herein will be useful, for example, in treatingbody wall defects such as herniated tissue in an abdominal or other bodywall, although inventive constructs and materials can be developed andused in many other medical contexts. In this regard, when used as amedical graft, inventive constructs can be utilized in any procedurewhere the application of the graft to a bodily structure providesbenefit to the patient.

The present invention also provides, in certain aspects, medicalproducts that include a graft construct as described herein in a sealedmedical package. In some forms of the invention, such medical productsinclude the graft construct enclosed in sterile condition within medicalpackaging. Illustratively, such a medical product can have packagingincluding a backing layer and a front film layer that are joined by aboundary of pressure-adhesive as is conventional in medical packaging,wherein the contents of the packaging are sealed between the backinglayer and front film layer. Sterilization of such a medical product maybe achieved, for example, by irradiation, ethylene oxide gas, or anyother suitable sterilization technique, and the materials and otherproperties of the medical packaging will be selected accordingly. Themedical packaging in other aspects can include a further, outer packagecontaining a dessicant, which can act to maintain a dry condition of theconstruct within the inner package when that inner package is somewhatvapor permeable.

In order to promote a further understanding of aspects of the presentinvention and features and advantages thereof, the following specificExamples are provided. It will be understood that these Examples areillustrative, and not limiting, of the invention.

EXAMPLE 1 Preparation of Distributed Depot ECM Construct

A. Preparation of ECM Laminate With Reservoirs

An 8-ply layered lyophilized SIS sheet was prepared. The sheet hadapproximately 12 mm diameter circular craters with raised walls, formedby an embossing mold compressed against the 8 SIS layer plies duringlyophilization under conditions to bond the layer plies to one anotherdehydrothermally. Each crater is formed to have a diameter of 12 mm-13mm with depth from bottom of the crater to the top of the surroundingwall of about 1 to 2 mm. The ECM material underlying the craters isdenser and less porous than the ECM material in surrounding regions dueto the compression of the material underlying the craters during drying.The formed SIS laminate sheet is perforated (1.5 mm diameter openperforations) and quilted with a 6-0 bioabsorable polyglycolic acid(PGA) thread, with a 4 mm quilt spacing in a pattern generally as shownin FIG. 1, and cut to size with an appropriate templates or die.

B. In-Situ Formation of Depot Deposits

A 20% w/v solution of poly-DL-Lactide-Co-Glycolide (PLGA) (50:50 PL:GA)in acetone is prepared and 15.68% w/w gentamicin sulfate powder(equivalent to 10.232% w/w gentamicin freebase) to the total solids(PLGA+gentamicin sulfate powder) is suspended in the acetone solution. Acontrolled volume of the solution was deposited into each crater on theSIS laminate sheet at a volume of 240 μL per crater to form each depot.The depots are dried on the SIS laminate sheet in a two stage process.The deposited material was first dried using air drying at roomtemperature, forming solidified depot material entraining air bubbles.In a second drying step, the deposited material was further dried byclamping the sheet between two porous inert polymeric sheets and dryingthe clamped construct in a vacuum oven under vacuum and heat (70° C.)for 4 days. The clamping and drying process compressed the depotmaterial, collapsing the air bubbles and reducing the thickness of thedepots.

EXAMPLE 2 Gentamycin Depot Elution Testing

A. Collection of Test Articles

For this study, since it was difficult to implant multiple of the whole13×22 cm devices prepared as in Example 1 with 33 depots (as shown inFIG. 1) each into the peritoneal cavity of a young 45 Kg domestic pig,the depot regions of the SIS laminate sheet were cut out with a 15 mmdiameter die. All such depot/ECM samples were collected from prepared6-7 laminate sheet devices and pooled to randomize. These were the testarticles. The test articles were packaged in small groups, labeled andETO sterilized.

B. In Vitro Elution Study

An in vitro elution test was carried out by soaking each test article in5 mL of phosphate buffered saline (PBS) solution (66.7 mM phosphatebuffer prepared by dissolving 1.65 g potassium phosphate monobasic and14.63 g sodium phosphate dibasic heptahydrate in 1000 mL of water) at37° C. for a specified time period. Then the same test article was movedinto a fresh vial of PBS and soaked at 37° C. for the next duration oftime point while maintaining traceability throughout. The soak solutionsthus collected were assayed for content of USP gentamicins using knownprocedures, by colorimetric treatment followed by HPLC and UV detection.The 3-4 major peaks representing the gentamicins were integrated toestimate the total gentamicin present in the solution. A five pointcalibration from 10 mcg/mL to 500 mcg/mL was run with every batch madefrom the same lot of gentamicin from vendor used to manufacture thedevices. An elution profile graph thus obtained is presented in FIG. 16.

C. In Vivo Elution Study

An in vivo elution study was conducted by implanting test articlescollected as described above intraperitoneally in a pig. Test articleswere implanted in the intraperitoneal abdominal space of a domesticswine such that the total dose of gentamicin freebase present in theimplants was equal to or greater than 1.5 times the highest documentedintra venous dose of 7 mg/kg body weight in a once-daily injectionregime. The serum gentamicin levels were tested at 0 (just pre-implant),4 hr, 24 hr, 48 hr, 72 hr, 120 hr, 290 hr post implant using a validatedLCMS assay. Gross necropsy was conducted after 290 hours time point andwhat was left of the implants was observed and collected. Un-implantedtest articles from the same lot were tested by using the above-notedcolorimetric USP content of gentamicins assay by HPLC/UV for determiningaverage gentamicin content and in vitro elution profile. Some of theexplanted test articles were also tested for average gentamicin contentleft after 290 hours in vivo. Similar content of gentamicin present inthe un-implanted depots vs. the explanted test articles was carried outusing liquid chromatography-mass spectrometry (LCMS).

More specifically, the test articles un-implanted were soaked in vialscontaining high purity water (HPW) at the rate of 5 mL per article. Theexplanted test articles obtained were separated if adhered to oneanother, rinsed quickly with 2-3 mL of HPW by dropper to remove anygentamicin already eluted and any excess blood present. The explantedsamples were then placed in vials containing HPW at 5 mL per article.

Vials containing test articles were closed and incubated at 80° C. with200 rpm orbital shaking for 46 hours to extract most of the gentamicinentrapped in the PLGA by degrading the polymer via acceleratedhydrolysis. After cooling, the exhaustive extraction solutions wereassayed for content of gentamicins as described above. An assessment ofthe data from these studies showed that each test article was originallyloaded with 4.522±0.306 mg gentamicin freebase. Based on the number oftest articles implanted (110) in the pig the total dose of gentamicinimplanted was 497.42±33.66 mg gentamicin freebase. This was estimated asa dose of 11.05±0.75 mg/Kg bw of the pig, which is approximately 1.6time greater than the maximum dose of gentamycin given once-dailyintravenously to humans.

The measured serum levels of gentamycin in the pig are shown in FIG. 17.Also, based on an analysis of 12 randomly selected un-implanted testarticles and 12 randomly-selected explanted test articles, an estimated16% of the gentamycin originally present remained in the explanted testarticles (after 290 hours of implantation in vivo).

All publications and patent applications cited in this specification areherein incorporated by reference as if each individual publication orpatent application were specifically and individually indicated to beincorporated by reference. Further, any theory, mechanism of operation,proof, or finding stated herein is meant to further enhanceunderstanding of the present invention, and is not intended to limit thepresent invention in any way to such theory, mechanism of operation,proof, or finding. While the invention has been illustrated anddescribed in detail in the drawings and foregoing description, the sameis to be considered as illustrative and not restrictive in character, itbeing understood that only selected embodiments have been shown anddescribed and that all equivalents, changes, and modifications that comewithin the spirit of the inventions as defined herein or by thefollowing claims are desired to be protected.

What is claimed is:
 1. An implantable device, comprising: a sheet graftmaterial having a top side and a bottom side; a plurality of drug depotsattached to the sheet graft material.
 2. The implantable device of claim1, wherein the sheet graft material comprises an extracellular matrixsheet material.
 3. The implantable device of claim 1 or 2, wherein: thesheet graft material has a porous matrix formed by a network of fibers,the porous matrix having pores formed between the fibers of the network;and the drug depots each comprise solid deposits including a polymericcarrier and a drug, the solid deposits each including a first portioninfiltrating pores of the porous matrix and a second portion external ofthe porous matrix.
 4. The implantable device of any preceding claim,wherein the drug is an antibiotic agent.
 5. The implantable device ofany preceding claim, wherein the drug is gentamycin.
 6. The implantabledevice of any preceding claim, wherein the depots are capable of elutingthe drug over a period of time greater than about 72 hours when thedevice is immersed in 66.7 mM phosphate buffered saline at 37° C.
 7. Theimplantable device of any preceding claim, wherein the depots areattached to the top side of the sheet graft material, and wherein thedepots in combination cover less than about 50% of the surface area ofthe top side of the sheet material.
 8. The implantable device of anypreceding claim, having from 2 to about 120 of said drug depots attachedto the sheet graft.
 9. The implantable device of any preceding claim,wherein: the sheet graft material has a porous matrix formed by anetwork of fibers, the porous matrix having pores formed between thefibers of the network; the drug depots each comprise solid depositsincluding a polymeric carrier and the at least one drug, the soliddeposits each including a first portion infiltrating pores of the porousmatrix and a second portion external of the porous matrix; the sheetgraft material has a thickness extending between the top surface and thebottom surface; and the first portions of the drug depots extend onlypartially through the thickness of the sheet graft material.
 10. Theimplantable device of any preceding claim, wherein: each said drug depotcovers a corresponding depot-bearing portion of the sheet graftmaterial, and preferably wherein each depot-bearing portion has asurface area constituting about 0.5% to about 15% of the surface area ofthe top surface of the sheet graft material, and more preferably whereineach depot-bearing portion has a surface area constituting about 2% toabout 10% of the surface area of the top surface of the sheet graftmaterial.
 11. The implantable device of claim 10, wherein: each saiddrug depot has a maximum thickness that is greater than a maximumthickness of the corresponding depot-bearing portion of the sheet graftmaterial covered by the depot.
 12. The implantable device of claim 10 or11, wherein: each said depot-bearing portion of the sheet graft materialis thinner than depot-free portions of the sheet graft materialoccurring between the depot-bearing portions.
 13. The implantable deviceof any one of claims 10 to 13, wherein: each said depot-bearing portionof the sheet graft material is denser than depot-free portions of thesheet graft material occurring between the depot-bearing portions. 14.The implantable device of any one of claims 10 to 14, wherein: each saiddepot-bearing portion of the sheet graft material is less porous thandepot-free portions of the sheet graft material occurring between thedepot-bearing portions.
 15. The implantable device of any precedingclaim, wherein: the drug depots are formed by a process including:depositing a flowable material including a carrier polymer and the atleast one drug onto the top side of the sheet graft material so as toform a plurality of deposited material portions; and hardening thedeposited material portions.
 16. The implantable device of any precedingclaim, wherein: the sheet graft material comprises one or moremembranous tissue layers harvested from a source tissue of awarm-blooded vertebrate animal and decellularized, the one or moremembranous tissue layers each having a porous matrix comprised of anetwork of collagen fibers, wherein the network of collagen fibersretains an inherent network structure from the source tissue.
 17. Theimplantable device of claim 16, wherein the one or more membranoustissue layers is effective when implanted in a subject to becomeinfiltrated with cells of the subject.
 18. The implantable device ofclaim 16 or 17, wherein the one or more membranous tissue layers iseffective when implanted in a subject to become replaced by tissue ofthe subject.
 19. The implantable device of any one of claims 16 to 18,wherein the one or more membranous tissue layers retains native collagenand native elastin from the source tissue.
 20. The implantable device ofany one of claims 16 to 19, wherein the one or more membranous tissuelayers retains from the source tissue least one of nativeglycosaminoglycans, native proteoglycans, and native growth factors. 21.The implantable device of claim 20, wherein the one or more membranoustissue layers retains from the source tissue native glycosaminoglycans,native proteoglycans, and native growth factors.
 22. The implantabledevice of any one of claims 16 to 21, wherein the sheet graft materialcomprises a laminate structure including a plurality of said membranoustissue layers.
 23. The implantable device of claim 22, wherein saidmembranous tissue layers are bonded to one another.
 24. The implantabledevice of claim 23, wherein said membranous tissue layers aredehydrothermally bonded to one another.
 25. The implantable device ofany one of claims 16 to 24, wherein said membranous tissue layers havenot been subjected to crosslinking by contact with a chemicalcrosslinking agent.
 26. The implantable device of any one of claims 16to 25, wherein said membranous tissue layers retain substantially theirnative level of crosslinking.
 27. The implantable device of anypreceding claim, wherein the bottom side of the sheet graft material isfree from any drug depots.
 28. The implantable device of any precedingclaim, wherein the bottom side of the sheet graft material has a surfaceprovided by one or more membranous tissue layers harvested from a sourcetissue of a warm-blooded vertebrate animal and decellularized, the oneor more membranous tissue layers each having a porous matrix comprisedof a network of collagen fibers, wherein the network of collagen fibersretains an inherent network structure from the source tissue.
 29. Amethod of manufacturing a medical graft, comprising: depositing at leastone volume of a flowable material comprising a drug onto at least oneregion of a graft material; and causing the flowable material to harden.30. The method of claim 29, wherein the graft material includes a porousmatrix, said method also comprising causing at least a portion of theflowable material to infiltrate pores of the porous matrix in the atleast one region.
 31. The method of claim 29 or 30, wherein the graftmaterial comprises one or more membranous tissue layers harvested from asource tissue of a warm-blooded vertebrate animal and decellularized,the one or more membranous tissue layers each having a porous matrixcomprised of a network of collagen fibers.
 32. The method of any one ofclaims 29 to 31, wherein said depositing comprises depositing aplurality of discrete volumes of the flowable material onto a pluralityof discrete regions of the graft material.
 33. The method of any one ofclaims 29 to 32, wherein the drug is an antimicrobial agent.
 34. Themethod of any one of claims 29 to 33, wherein said causing comprisesremoving a solvent from the flowable material.
 35. The method of any oneof claims 29 to 34, wherein the graft material comprises anextracellular matrix sheet material.
 36. The method of any one of claims29 to 35, wherein said at least one region comprises a reservoir formedin the graft material.
 37. The method of any one of claims 29 to 36,wherein said causing forms a hardened material, and wherein the methodalso comprises reshaping the hardened material.
 38. The method of claim37, wherein said reshaping includes reducing the thickness of thehardened material.
 39. The method of claim 37 or 38, wherein saidreshaping includes smoothing an upper surface of the hardened material.40. The method of claim any one of claims 37 to 39, wherein the hardenedmaterial includes pores, and wherein said reshaping includes collapsingthe pores.
 41. The method of any one of claims 37 to 40, wherein saidreshaping includes compressing the hardened material against a surface.42. The method of any one of claims 29 to 41, wherein said graftmaterial is a flexible sheet graft material.
 43. The method of any oneof claims 29 to 41, conducted so as to form a plurality of drug depotwafers from the flowable material, the drug depot wafers attached to thegraft material.
 44. The method of claim 43, wherein the medical grafthas a total dose of the drug, and wherein said plurality of drug depotwafers includes 2 to 100 drug depot wafers incorporating at least 50% ofthe total dose of the drug.
 45. The method of claim 44, wherein saidplurality of drug depot wafers includes 10 to about 60 drug depot wafersincorporating at least 80% of the total dose of the drug.
 46. The methodof any one of claims 29 to 45, wherein the graft material is a sheetgraft material, and wherein the method is conducted so as to form aplurality of discrete drug depots from the flowable material, whereinthe drug depots have top surfaces that, taken together, define a surfacearea that is less than 50% of the surface area defined by the topsurface of the of the sheet graft material.
 47. An implantable device,comprising: a graft material having a porous matrix formed by a networkof fibers, the porous matrix having pores formed between the fibers ofthe network; and one or more drug depots including a polymeric carrierand a drug, the one or more drug depots including a first portioninfiltrating pores of the porous matrix and a second portion external ofthe porous matrix.
 48. The implantable device of claim 47, wherein thegraft material comprises an extracellular matrix material.
 49. Theimplantable device of claim 47 or 48, wherein the drug is an antibioticagent.
 50. The implantable device of any one of claims 47 to 49, whereinthe drug is gentamycin.
 51. The implantable device of any one of claims47 to 50, wherein the one or more drug depots are capable of eluting thedrug over a period of time of at least about 72 hours when the device isimmersed in aqueous phosphate buffered saline at 37° C.
 52. Theimplantable device of any one of claims 47 to 51, wherein the one ormore drug depots are attached to a top side of the graft material, andwherein the depots in combination cover less than about 50% of thesurface area of the top side of the graft material.
 53. The implantabledevice of any one of claims 47 to 51, wherein from 2 to no more than 100of said drug depots incorporate at least 50% of a total dose of the drugon the device.
 53. The implantable device of any one of claims 47 to 51,wherein from 5 to about 80 of said drug depots incorporate at least 80%of a total dose of the drug on the device.
 54. The implantable device ofany one of claims 47 to 51, wherein from 10 to about 60 of said drugdepots incorporate at least 99% of a total dose of the drug on thedevice.
 55. The implantable device of any one of claims 47 to 54,wherein: said first portion of the one or more drug depots extends onlypartially through a thickness of the graft material.
 56. The implantabledevice of any one of claims 47 to 55, wherein said sheet graft comprisesa laminate of a plurality of extracellular matrix layers.
 57. Theimplantable device of claim 56, wherein said extracellular matrix layershave a native collagen architecture retained from an animal sourcetissue for the extracellular matrix layers.
 58. The implantable deviceof claim 56 or 57, wherein said extracellular matrix layers retain atleast one native growth factor from an animal source tissue for theextracellular matrix layers.
 59. The implantable device of any one ofclaims 1 to 28 or 47 to 58, wherein the graft material includes asynthetic polymeric mesh and at least one extracellular matrix sheet.60. The implantable device of claim 59, wherein the graft materialincludes the synthetic polymeric mesh sandwiched between a firstextracellular matrix sheet and a second extracellular matrix sheet. 61.A method for treating a patient, comprising implanting in the patient animplantable device according to any one of claims 1 to 28 or 47 to 60.62. The method of claim 61, wherein said implanting comprises implantingthe device so as to support soft tissue of the patient.
 63. The methodof claim 62, wherein said implanting is to repair a hernia.